Maternal high fat diet promotion of mammary tumor risk in adult progeny is associated with early expansion of mammary cancer stem‐like cells and increased maternal oxidative environment

Abstract

Many adult chronic diseases might be programmed during early life by maternal nutritional history. Here, we evaluated effects of maternal high fat diet on mammary gland development and tumor formation in adult progeny. Female Wnt‐1 transgenic mice exposed to high fat (HFD, 45% kcal fat) or control Casein (CAS, 17% kcal fat) diets in utero and during lactation were weaned to CAS diet at postnatal day 21 (PND 21). Relative to the CAS group, offspring exposed to maternal HFD had higher body and mammary tissue weights and elevated blood sugar and serum insulin levels at weaning and at PND110 and greater terminal end bud numbers at PND30. Mammary expression of tumor suppressors PTEN and p53 and pro‐apoptosis Bcl‐2 genes were lower in progeny exposed to maternal HFD. Mammary tumor latency was also lower (P=.01) in HFD (115±21 d) than CAS (190±13 d) offspring but tumor incidence and growth did not differ between groups. Epithelial cells from pre‐neoplastic mammary tissues showed expansion of the CD29highCD24+ (basal) and Thy1+CD29highCD24+ (cancer stem cell) subpopulations with maternal HFD exposure. Dams exposed to HFD had lower serum glutathione (GSH/GSSG) and cysteine (cysteine/cystine) oxidative ratios than CAS dams at weaning, but the two groups did not differ in body weights and insulin levels. Thus, maternal high fat diet, by altering early mammary development, may constitute a major risk factor for adult breast cancer.Grant Funding Source: USDA‐CRIS 6251–51000‐005–004S, Arkansas Breast Cancer Research Program, Arkansas Biosciences Institute